Patients with schizophrenia commonly develop alcohol use disorders, which worsen the course of schizophrenia. While typical antipsychotic drugs (e.g., haloperidol -- HAL) appear to be of little value in controlling alcohol use in these patients, the atypical antipsychotic clozapine (CLOZ), although prescribed infrequently because of its toxicity, substantially decreases their alcohol use. We have proposed that a dysfunction in brain reward circuitry underlies alcohol use in this population, and that: (1) HAL does not decrease alcohol use in this population because it does not restore the normal function of the reward circuitry (in part because of its potent dopamine [DA] D2 receptor antagonism);but (2) that CLOZ, through its pharmacologic effects (including its weak DA D2 receptor antagonism, its potent norepinephrine (NE) alpha 2 receptor antagonism, and its NE reuptake inhibition), has a normalizing effect on this circuit. To further elucidate the effects of CLOZ and HAL on alcohol use, we have performed studies in alcohol preferring rodents. Preliminary data from these rodent studies, indicating that (1) CLOZ decreases their alcohol drinking more than HAL;(2) adding the potent DA D2/D3 receptor antagonist raclopride to CLOZ decreases CLOZ's effect on alcohol drinking;and (3) combining HAL with a NE 1-2 receptor antagonist or a NE reuptake inhibitor increases HAL's ability to decrease alcohol drinking, provide support for our proposal about the actions of CLOZ and HAL on alcohol drinking. In this second revision of a two year, "proof of concept" application, we seek to extend our preliminary data. Our overarching hypothesis is that CLOZ's effect in alcohol-preferring rodents, as in patients with schizophrenia and co-occurring alcohol use disorder, relates to its actions on DA and NE systems as noted above, actions that can be mimicked through creation of agents that have CLOZ-like pharmacologic activity. This proposal seeks to more fully elucidate this hypothesis, and to provide data enabling further research related to the biologic basis of CLOZ's effect on alcohol drinking. The long-term goal of our research program is to develop better treatments (e.g., safer CLOZ-like medications) for alcohol use disorder in patients with schizophrenia. The specific aims of this proposal, involving research in hamsters, are: (1) To extend and further elucidate our preliminary data suggesting that CLOZ's ability to decrease alcohol drinking relates in part to its weak DA D2 receptor antagonism and to assess the role of its potent NE 1-2 receptor antagonism. (2) To extend and further elucidate our preliminary data suggesting that HAL's ability to decrease alcohol drinking in rodents can be amplified by combining it (in low dose, to provide a weak DA D2 receptor blockade) with a NE 1-2 receptor antagonist or a NE reuptake inhibitor. (3) To explore the effect of the combination of a DA D2 receptor antagonist, a NE 1-2 receptor antagonist and a NE reuptake inhibitor on alcohol drinking in rodents. PUBLIC HEALTH RELEVANCE: Public health significance: Alcohol use disorder is common in schizophrenia and worsens the course of this severe psychiatric disorder. While most antipsychotics do not lessen alcohol use in schizophrenia, the atypical antipsychotic clozapine does, although the mechanism by which this occurs is uncertain. While clozapine's toxicity severely restricts its use, understanding its mechanism of action, as proposed here, may lead to development of new drugs, safer than clozapine, which could limit alcohol use disorder in patients with schizophrenia.